D ON T USE F ORMULARY KBr – Respiratory toxic in Cats Lamotrigine (Lamictal) – cardiotoxic in dogs Verapamil – no effect Dilantin Depakote/Depakene Primidone
N EW S EIZURE P EARLS NCSU - ABCB1 Gene Defect – Easier to control epileptics Denmark - Belgian Shepherd Epilepsy Study – normal life span but epilepsy percentage of reasons for death (also 2 SUEDS). England – 41% of epileptics had clusters – no age, breed predilection but intact animals had more clusters Korea – Zonisamide 60% effective sole agent
Auburn – Seizure control - 85% pheno 52% KBr Minnesota – Status – 60mg/kg Keppra – once significant improvement in control England – Juvenile onset <1y seizures – 22% remission rate (humans 60%). NCSU - The pharmacokinetics of levetiracetam in healthy dogs concurrently receiving phenobarbital. PB lowered LEV levels
Germany - CSF Glucose – not indicative of infection – just inflammation TAMU – PSS surgery – pre treat with Keppra no seizures vs 4/84 Denmark – PBGV – 9% epileptics England – Seizures and brain tumors - 68 dogs (42 had seizures 24 did not). Contrast enhancement, frontal lobe and herniation - risks
LV Nevada - Canine and feline epileptic seizures and the lunar cycle: 2,507 seizures ( ). 211 dogs – no correlation Penn - A novel implanted device to wirelessly record and analyze continuous intracranial canine EEG. Treat only when going to have seizure! England - Effects of essential fatty acid supplementation in dogs with idiopathic epilepsy: a clinical trial. No effect – blinded placebo controlled.
Germany - Add-on treatment with verapamil in pharmacoresistant canine epilepsy. – Bradycardia and hypotension – no effect
B REATH HOLDING E PISODES R EFLEX SYNCOPE BENIGN PAROXYSMAL VERTIGO VASOVAGAL ATTACKS SLEEP DISORDERS PSEUDOSEIZURES MUNCHHAUSEN SYNDROME EEG – 20% HAVE NORMAL EEG T RULY NORMAL OR OUT OF REACH OF ELECTRODES IMPROVE BY SLEEP DEPRIVATION ; FLASHING LIGHTS ; HYPERVENTILATION ; PROLONGED PERIODS Non Epileptic Attacks
S POT 12 year old Chihuahua Cluster/isolated seizures Meds: Phenobarbital, Kbr, gabapentin, clorazepate Zonisamide
R EX 9y Lab Mix Pheno, Kbr, Lyrica, gabapentin, Zonisamide, valproic acid, acetazolamide, banzel
Generalized seizures. Absence seizures, appear to be staring into space These seizures are sometimes referred to as petit mal seizures, which is an older term. Tonic seizures cause stiffening of muscles of the body Clonic seizures cause repeated jerking movements of muscles on both sides of the body. Myoclonic seizures cause jerks or twitches of the upper body, arms, or legs. Atonic seizures cause a loss of normal muscle tone - will fall down or may drop head involuntarily. Tonic-clonic seizures cause a mixture of symptoms, older term: grand mal seizures.
Simple focal motor seizure Remain conscious - sudden focal jerking of a muscle group Complex focal seizure Change in or loss of consciousness. dreamlike experience. may display strange, repetitious behaviors (automatisms) such as blinks, twitches, mouth movements, walking in a circle.
H UMAN E XPERIENCE 60% of childhood epilepsy resolves and 60% controlled with monotherapy 60 percent of people with epilepsy have focal seizures. These seizures are frequently described by the area of the brain in which they originate.
Anticonvulsant History Bromide first used in the late 1800s Negative side effects made it a less than ideal medication Discontinued in 1912 in US Reappeared in 1980s for veterinary use Used in Europe for people Phenobarbital 1912 Despite its shortcomings, phenobarbital became the main drug prescribed for epilepsy for the next 26 years.
Anticonvulsant History Phenytoin (Dilantin) was introduced in 1938 is still a major drug used today in human seizure control. From 1945 to 1960 a series of anticonvulsant drugs based on trimethadione (Tridione) Diazepam 1963 Carbamazepine (Tegretol) 1974 Valproic acid (Depakene) 1978
Drugs not routinely used in veterinary medicine Primidone Carbamazepine (Tegretol, Carbatrol) Phenytoin (Dilantin) Valproic acid (Depakene)/Divalproex (Depakote) Ethosuximide (Zarontin)/Methsuximide (Celontin)
Anticonvulsant Recent History In the 1990s another crop of new medications appeared These drugs are reported to have fewer side effects, but with similar efficacy (questionable) in the control of seizures
When/Why to Start Treatment More than 1 seizure in a 4-6 week period Active intracranial disease (neoplasia, inflammation) Cluster seizures Status epilepticus
Clinical findings, treatment, and outcome of dogs with status epilepticus or cluster seizures: 156 cases ( ). J Am Vet Med Assoc Nov 15;215(10): Bateman SW, Parent JM.Bateman SWParent JM Underlying causes of seizures were primary epilepsy (26.8%), secondary epilepsy (35.1%;), reactive epileptic seizures (6.7%), primary or secondary epilepsy with low serum antiepileptic drug concentrations (5.7%), and undetermined (25.8%). 186 resulted in admission to the ICU. CRI of diazepam or phenobarbital Of 194 admissions, 74.7% (145) resulted in discharge from the hospital 2.1% (4) in death, and 23.2% (45) in euthanasia. Poor outcome (death or euthanasia) was significantly associated with GME, loss of seizure control after 6 hours of hospitalization, and the development of partial status epilepticus.
Felbamate (Felbatol) Dicarbamate medication approved for use in 1993 Increases seizure threshold and prevents seizure spread by reducing excitatory neurotransmission in the brain In dogs used as an add on for refractory seizures, not generally used as monotherapy Generic 9/2011.
Felbamate (Felbatol) Undergoes hepatic metabolism by P 450 system and is also excreted by the kidneys T 1/2 5-6 hours with steady state reached in 1-2 days Dose mg/kg q8 hours, has been used as high as 65 mg/kg Non sedating with a high margin of safety Idiosyncratic aplastic anemia secondary to bone marrow suppression and liver toxicity Similar but rare and reversible hepatotoxicity and blood dyscrasias seen in dogs Monitoring Parameters CBC, chemistry at 1 month after starting treatment, then q 3-6 months
Treatment of partial seizures and seizure-like activity with felbamate in six dogs. J Small Anim Pract Aug;42(8):403-8.Ruehlmann D, Podell M, March P.Ruehlmann DPodell MMarch P Six dogs with partial seizures or partial seizure-like activity Median duration of therapy was nine months (range two to 22 months). All dogs experienced a reduction in seizure frequency after felbamate administration. Reversible haematological adverse effects were detected in two dogs, with one dog developing concurrent keratoconjunctivitis sicca.
Gabapentin (Neurontin) Designed to mimic GABA, but does not have similar pharmacological properties of GABA nor does it bind to GABA receptors Facilitates transport of GABA out of cells to act on the GABA A receptor to increase inhibitory activity and block sodium channels Undergoes partial hepatic metabolism, but mostly excreted by the kidneys
Treatment with gabapentin of 11 dogs with refractory idiopathic epilepsy. Vet Rec Dec 23-30;159(26): TPlatt SR, Adams V, Garosi LS, Abramson CJ, Penderis J, De Stefani A, Matiasek L. 11dogs with refractory idiopathic epilepsy All had generalised tonic-clonic seizures and had been treated with a combination of phenobarbital and potassium bromide Compared for the three months before and after Six of the dogs showed a positive response. minimum 50 per cent reduction in the number of seizures per week was interpreted as a positive response Mild side effects of ataxia and sedation were observed in five of the dogs, but they were not severe enough to warrant the treatment being discontinued during the trial.
Improving seizure control in dogs with refractory epilepsy using gabapentin as an adjunctive agent Aust Vet J Oct;83(10): Govendir M, Perkins M, Malik R. Faculty of Veterinary Science, Building B14, The University of Sydney, New South Wales DESIGN: 17 dogs;16 of which have idiopathic epilepsy. PROCEDURE: Patients were stabilised using phenobarbitone and/or potassium bromide and dosed additionally with gabapentin at 35 to 50 mg/kg/d (divided twice or three times daily) for 4 months. RESULTS: There was no significant decrease in the number of seizures over the study period for the entire cohort, however three dogs stopped seizuring completely. Side effects observed - sedation and hind limb ataxia. Long-term, a further two patients became seizure free and ten patients remained on gabapentin indefinitely. No long-term side effects have become apparent. CONCLUSION: Addition of gabapentin increased the interictal period and shortened the post-seizure recovery in some canine epileptics. In some dogs, seizures were prevented completely, while in others there was an increase in interictal period.
Zonisamide (Zonegran) Sulfonamide based drug that became available for use in 2000 Is used in human for treatment of focal and generalized seizures with minimal side effects Works by blocking the propagation of epileptic discharges and suppressing focal epileptogenic activity
Zonisamide (Zonegran) Metabolized mainly by hepatic microsomal enzymes, but does not induce P 450 system T 1/2 15 hours Dose 10 mg/kg q 12 hours, but if add on treatment with drugs inducing hepatic enzymes, decrease dose to 5 mg/kg q 12 hours High margin of safety Can be used as monotherapy Side effects Transient sedation, ataxia, inappetance, metabolic acidosis, liver intoxication, bone marrow Can reduce side effects by gradually increasing the dose If being used with phenobarbital, recommend reducing phenobarbital dose by 25%
Zonisamide therapy for refractory idiopathic epilepsy in dogs. J Am Anim Hosp Assoc Jul-Aug;40(4): Dewey CW, Guiliano R, Boothe DM, Berg JM, Kortz GD, Joseph RJ, Budsberg SC. Department of Surgery, Long Island Veterinary Specialists, Plainview, New York Twelve dogs with poorly controlled idiopathic epilepsy were entered into a prospective, open-label, noncomparative study. Oral zonisamide was administered as an additional therapy at a dosage adequate to achieve serum drug concentrations of 10 to 40 microg/mL. Seizure frequency before and after initiation of zonisamide therapy was recorded. A dosing interval of q 12 hours was sufficient to maintain serum zonisamide concentrations within the therapeutic range. The mean dosage of zonisamide required was 8.9 mg/kg q 12 hours. Seven (58%) dogs responded favorably, experiencing a mean reduction in seizures of 81.3%. Five dogs had an increase in seizure frequency. Mild side effects (e.g., transient sedation, ataxia, vomiting) occurred in six dogs.
Prospective study of zonisamide therapy for refractory idiopathic epilepsy in dogs J Small Anim Pract Mar;48(3): von Klopmann T, Rambeck B, Tipold A. Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Bischofsholer Damm Hannover, Germany. METHODS: Thirteen dogs fulfilled the inclusion criteria of poor seizure control despite adequate serum levels of phenobarbital, potassium bromide or both. One further dog was treated with zonisamide as monotherapy because of severe blood dyscrasia due to phenobarbital treatment.. RESULTS: Data of 11 dogs could be evaluated: nine of them were responders. The median reduction of seizure frequency of all dogs on zonisamide add-on therapy was 70 per cent (range 14 to 100 per cent). Only transient central nervous system side effects were reported. No further increase of liver enzymes occurred. In three of the responder dogs, seizure control subsided after individual time periods (between 69 days and seven months).
Topiramate (Topamax) Sulfamate substituted monosaccharide Blocks seizure spread by rapidly potentiated GABA activity in the brain In people it is used for generalized and partial seizures In people it is primarily excreted by the kidneys unchanged T 1/ hours (people), 2-4 hours (dogs), steady state reached in 1-3 days Dose 2-10 mg/kg q 12 hours, best to start low Side effects GI upset, inappetence, irritability, ataxia
Levetiracetam (Keppra) Synaptic Vesicle Protein 2 A, is required for normal nervous system functioning and is the binding site of the anti- epilepsy drug levetiracetam Mostly excreted unchanged in the urine, the remainder is hydrolyzed in the serum and by other organs No hepatic metabolism in humans or dogs T 1/2 3-4 hours but may exert anticonvulsant effects that last longer than its presence in the bloodstream Dose 20 mg/kg q 8 hours
The efficacy and tolerability of levetiracetam in pharmacoresistant epileptic dogs. Vet J Jun;176(3): Epub 2007 Apr 30. Volk HA, Matiasek LA, Luján Feliu-Pascual A, Platt SR, Chandler KE.Volk HAMatiasek LALuján Feliu-Pascual APlatt SRChandler KE 8/14 dogs responded significantly to the treatment and seizure frequency was reduced by 50%. In dogs that remained refractory, the dosage was increased to 20 mg/kg TID for 2 months. One further dog responded to levetiracetam treatment. Levetiracetam responders had a significant decrease in seizure frequency of 77% (7.9+/-5.2 to 1.8+/-1.7 seizures/month) and a decrease in seizure days per month of 68% (3.8+/-1.7 to 1.2+/-1.1 seizure days/month). However, 6/9 responders experienced an increase in seizure frequency and seizure days after 4-8 months continuing with the levetiracetam treatment at the last effective dosage.
Levetiracetam as an adjunct to phenobarbital treatment in cats with suspected idiopathic epilepsy. J Am Vet Med Assoc Mar 15;232(6): Bailey KS, Dewey CW, Boothe DM, Barone G, Kortz GD.Bailey KSDewey CWBoothe DMBarone GKortz GD ANIMALS: 12 cats suspected to have idiopathic epilepsy that was poorly controlled with phenobarbital or that had unacceptable adverse effects PROCEDURES: Cats were treated with levetiracetam (20 mg/kg [9.1 mg/lb], PO, q 8 h). RESULTS: Median seizure frequency prior to treatment with levetiracetam (2.1 seizures/mo) was significantly higher than median seizure frequency after initiation of levetiracetam treatment (0.42 seizures/mo0 7 of 10 cats were classified as having responded Two cats had transient lethargy and inappetence.
Pregabalin (Lyrica) Structural analogue to GABA No effect on GABA receptors Renal excretion T 1/2 6 ½ hours (people) Current study in dogs dose 2-4 mg/kg q 12 hours
Pregabalin as an adjunct to phenobarbital, potassium bromide, or a combination of phenobarbital and potassium bromide for treatment of dogs with suspected idiopathic epilepsy. J Am Vet Med Assoc Dec 15;235(12): Dewey CW, Cerda-Gonzalez S, Levine JM, Badgley BL, Ducoté JM, Silver GM, Cooper JJ, Packer RA, Lavely JA. Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY OBJECTIVE: Pregabalin as an adjunct to phenobarbital, potassium bromide ANIMALS: 11 client-owned dogs RESULTS: Seizures were significantly reduced (mean, 57%; median, 50%) after pregabalin administration 9 dogs that completed the study; 7 were considered responders with mean and median seizure reductions of 64% and 58%, respectively. Adverse effects for pregabalin were reported in 10 dogs.
R UFINAMIDE (B ANZEL ) No published clinical studies in dogs One published pharmacokinetic study Dose 10-20mg/kg BID Clinical experience – good
Rufinamide: a new antiepileptic medication for the treatment of seizures associated with lennox-gastaut syndrome. Ann Pharmacother Apr;44(4): Epub 2010 Mar 16. Wisniewski CS.Wisniewski CS STUDY SELECTION AND DATA EXTRACTION: Published controlled trials DATA SYNTHESIS: Rufinamide is a new antiepileptic agent that differs structurally from other antiepileptic drugs and is approved as adjunctive therapy for Lennox- Gastaut syndrome (LGS). I prolonging sodium channel inactivity, stabilizing cell membranes It is absorbed and metabolized extensively, then excreted renally as an inactive metabolite. Clinical trials show that adjunctive rufinamide is effective at reducing seizure frequency in patients with LGS and refractory partial seizures rufinamide is well tolerated, causing headache, dizziness, and fatigue at rates of >10%. CONCLUSIONS: Data show that rufinamide is safe and effective as an adjunctive agent for LGS and may be used to treat partial seizures.
L ACOSAMIDE (V IMPAT ) Renal excretion No clinical studies in dogs
Epilepsy Surgery 3 drug failures Impaired consciousness, injury, stigmatizing behavior (disrobing, uttering obscenities), noxious auras (vomiting/fear) At least 1/month CPS and Tonic/Clonic – most common 50% of intractable patients have surgically remediable epilepsy Control after sx 58% seizure free vs 8% with continued drug management in one study Workup – EEG, MRI, neuropsychological evaluation. If not definitive then invasive EEG, nuclear med (PET, SPECT) and WADA (sodium amylobarbital) test.
Syndromes Amenable to Surgery: Mesial Temporal Lobe Epilepsy (hippocampus and amygdala); Frontal Lobe epilepsy; Lesional Partial Epilepsy; Crytogenic Neocortical Epilepsy Surgery options Lesionectomy, lobectomy, hemispherectomy, subpial transections, corpus collosotomy Success rates; Anterior temporal lobectomy 70% success; other areas 40-60% seizure free; CC 50-80% reduction Deficits – some are expected. Many transient. 50% minor field of vision loss. 1-2% permanent morbidity.
E LECTROSTIMULATION PROCEDURES Vagal Nerve Stimulations Deep Brain Stimulations
VNS Does not eliminate seizures 27-64% reduction
Use of vagal nerve stimulation as a treatment for refractory epilepsy in dogs. JAVMA 2002 Oct 1;221(7): Munana KR, Vitek SM, Tarver WB, Saito M, Skeen TM, Sharp NJ, Olby NJ, Haglund MM ANIMALS: 10 dogs with poorly controlled seizures. RESULTS: No significant difference overall 13-week treatment. During the final 4 weeks of the treatment period, a significant decrease in mean seizure frequency (34.4%) was detected. Complications included transient bradycardia, asystole, and apnea during intraoperative device testing, and seroma formation, subcutaneous migration of the generator, and transient Horner's syndrome.
Personal Experience 1 DDB (Gaia) Reason: Spinal deformity and epilepsy Outcome: Initially good (lowered meds); lead complication 1 Husky (Stoli) Severe clusters – numerous medications Short lived improvement then DOA
Risks of Hemispherectomy Hemorrhage is a risk for hemispherectomy. Disseminated intravascular coagulation "Aseptic meningitis," Hydrocephalus, 20–30% of patients. Death from surgery - approximately 2% of patients.
Recovery of functions after neonatal or adult hemispherectomy in cats. III. Complex functions: open field exploration, social interactions, maze and holeboard performances. Behav Brain Res May;20(2): Burgess JW, Villablanca JR, Levine MS. Complex behavioral patterns were studied in cats with removal of the entire left cerebral hemisphere neonates (n = 10) or adults (n = 11); control (n=24) Adult cats showed decreased open field activity in locomotion, rearing and sniffing. Kittens showed similar deficits at 100 days of age by 150 days of age they resembled normal littermates in all 3 measures.
Recovery of function after neonatal or adult hemispherectomy in cats: Behav Brain Res Mar;19(3): Villablanca JR, Burgess JW, Olmstead CE. Cats with removal of the left hemitelencephalon (hemispherectomy) as neonates (n = 12) or in adulthood (n = 14), were compared using a battery of 16 neurological and behavioral tests given when they were young adults (kittens) or at least 5 months after the lesion (adults). The neonatal-lesioned subjects grew normally and performed markedly and significantly better than adult- lesioned cats None of the animals recovered tactile placing of the right forelimb or a normal vision in the right visual field. Overall recovery was outstanding for all cats Neonatal-lesioned were hard to differentiate from intact controls in their spontaneous, daily activities.
Proc Staff Meet Mayo Clin Jan 7;34(1): Operative technics and principles utilized in total hemispherectomy in the monkey and the dog. WHITE RJ, MACCARTY CS, GRINDLAY JH, SCHREINER LH.
Absence of temporal lobe epilepsy pathology in dogs with medically intractable epilepsy. J Vet Intern Med Jan-Feb;16(1):95-9. Buckmaster PS, Smith MO, Buckmaster CL, LeCouteur RA, Dudek FE.Buckmaster PSSmith MOBuckmaster CLLeCouteur RADudek FE Department of Comparative Medicine, Stanford University School of Medicine, CA Temporal lobe epilepsy is the most common type of epilepsy in adult humans, it is frequently resistant to anticonvulsant therapy We sought to test the hypothesis that dogs with medically intractable epilepsy have temporal lobe epilepsy. The hippocampi of 6 dogs that were euthanized because of chronic, recurrent seizures were compared with those of 8 nonepileptic controls. These findings demonstrate a lack of hilar neuron loss and granule cell axon reorganization, suggesting that temporal lobe epilepsy is not a common cause of medically intractable epilepsy in dogs.
Callosotomy J Neurosurg Sci Mar;41(1):51-7. Callosotomy for intractable epilepsy: overall outcome. Rougier A, Claverie B, Pedespan JM, Marchal C, Loiseau P. Clinique Universitaire de Neurochirurgie, Hôpital Pellegrin-Tripode, Bordeaux, France. Atonic and tonic astatic seizures characterized both by clinical and electroencephalographical specific patterns, are the most responsive. > 50% reduction in seizure frequency to a complete cessation, in 60 to 80% of the patients. For tonic-clonic seizures, favorable outcome fluctuates from 40% to 80% principally according to the extension of the section. Other types of seizures are not indicated for callosotomy even though some improvement may be observed.
M ULTIPLE S UBPIAL T RANSECTIONS
Y OUNG D OG - H EALTHY Phenobarbital Potassium bromide Zonisamide Levetiracetam
OLD DOG STRUCTURAL PROBLEM Levetiracetam (Keppra) or zonisamide (Zonegran) Felbamate (Felbatol)
L IVER D ISEASE Levetiracetam (Keppra) or Potassium Bromide Gabapentin (Neurontin) Pregabalin (Lyrica) Topiramate (Topimax)
R EFRACTORY C OMBOS Phenobarbital and levetiracetam Phenobarbital and KBr (side effects) Zonisamide and KBr Zonisamide and levetiracetam Phenobarbital and zonisamide (double zonisamide)
S EVERELY R EFRACTORY R EFER ? Rufinamide/Banzel Lacosamide Clobazam Surgery